The present invention relates to microcapsules, spherical microparticles, constituted by a jacket of a gastro-resistant coating material constituting the reservoir of an oily liquid that it contains.
The present invention also relates to a finished product in the form of a powder formed of microcapsules according to the invention providing a delayed release of an active principle of an oily nature.
Lastly the present invention relates to a method for the preparation of microcapsules and of a finished product in powder form according to the invention.
In therapeutics or in preventive medicine a need is frequently found for a technique enabling the release of an active principle after a prolonged stay in the organism.
In galenic pharmacy, the most frequent methods enabling these effects to be produced are: 1) Microencapsulation by coacervation with gastroresistant polymers (H. P. MERKLE and SPEISER, J. Pharm. Sci. 62:1444-1448 (1973); L. A. LUZZI and R. J. GERRAUGHTY, J. Pharm. Sci. 53:429-431 (1964); J. W. BEYGER and J. G. NAIRN J. Pharm. Sci. 75, 6:573-578 (1986). These methods are delicate to practise on an industrial scale and in addition often call for organic solvents which are the cause of toxic residues or call for the employment of amounts of substances which render the finished product economically uninteresting. 2) On the other hand, there exists another method equally very widespread, which enables formulations with delayed release to be obtained. This method is however only applicable to active principles in solid form [powder, granules, or tablets] and it consists of a coating [in a fluidized air bed or in a cyclone] by projection of a solution of enteric polymer onto cores suspended in a bed of hot air (H. C. CALDWELL and E. ROSEN J. Pharm. Sci. 53:1387-1391 (1964); M. J. ROBINSON, G. M. GRASS and R. J. LANTZ J. Pharm. Sci. 57:1983-1988 (1968); K. LEHMANN, D. DREHER, Pharm. Ind. 34:894-899 (1972); W. ROTHE, G. GROPPENBACHER Pharm. Ind. 34 (11a):892-894 (1972)
This technique is however not applicable when it is a matter of encapsulating an active principle directly in liquid form.
In the food industry, the technique of encapsulation of food oils, flavorings or colorings by polymers which are not gastro-resistant such as gum arabic, maltodextrin, gelatin, is very widespread. These applications are realized, in most cases, by the method of spraying or "spray drying" (ANANDARMAN, E. B. WILLIAM and G. REINECCIUS Perf. Flav. 8:49-56 (1983); K. IWAMI, M. HATTORI, S. NAKATANI and F. IBUKI, Agric. Biol. Chem., 51(12):3301-3307 (1987).
This technique for the preparation of microcapsules by drying by atomization has never been proposed and applied with gastro-resistant polymers in particular such as CAP or Eudragit R taking into account the actual practical difficulties. These polymers have in fact a tendency to be in thread form and to block the atomizer turbine taking into account their viscosity which is too high.
The patent EP 225 303 describes oil microcapsules which are prepared in aqueous emulsion in a solution of gastro-resistant polymers by the conventional technique of coacervation or by "spray-coating". The "spray-coating" technique is a technique of vaporization of the polymer onto a powder in a fluidized bed. The technique described in this patent relates to tablets, capsules or capsules which can contain oil prepared in two phases, coating by a gastro-resistant polymer only taking part after the preparation of the gelule or capsule proper.
The patent GB 2,223.943 also describes microcapsules. Here again it is a matter of gelules, particularly of gelatin, filled with oil which are only afterwards coated with a gastro-resistant polymer.
The patent EP 336 662 describes the preparation of microcapsules containing oil prepared in a first phase from an oil-in-water emulsion [oil/alginate] which is sprayed cold into a solution of CaCl.sub.2, which causes precipitation of the polymer around the oil droplets. These microcapsules are then suspended in a solution of gastro-resistant polymer which is precipitated around the microcapsules by the addition of acid. It is hence a matter here also of an encapsulation technique by chemical coacervation.
It is an object of the present invention to obtain in original manner a gastro-resistant powder constituted by microcapsules comprising an oily liquid.
To do this, the present invention provides a method for the preparation of microcapsules constituted by a solid jacket of a coating material comprising at least one gastro-resistant polymer, said solid jacket containing an oily liquid, said method being characterized in that drying by atomization is carried out [also called spray-drying], by means of an atomizer, or an emulsion of the oil-in-water type obtained from said oily liquid and of an aqueous solution of the coating material comprising the one or more gastro-resistant polymers in admixture with at least one emulsifier.
In the present application, by coating material it is intended to denote polymers, including here gums or synthetic or natural resins, which are physiologically acceptable, or even proteins.
The present invention is based on physical encapsulation by direct atomization [drying] in a drying tower of an oil/water emulsion formed by the active principle and the aqueous solution of gastroresistant polymer in admixture with other conventional polymers so as to recover directly in one step a gastro-resistant dry powder, formed of microcapsules.
The method according to the invention therefore involves the operation of a device for drying by atomization. These devices are well known to the technicians skilled in the art. They are composed, for example, of a high tower at the top of which the liquid phase, in the event the emulsion, is finally dispersed by passage through a nozzle sprayer or rotary disk sprayer. The droplets formed pass through an air flow established in co- or in counter-current and taken to a controlled temperature particularly 140 degrees C. The microcapsules solidify and are recovered at the base of the spray chamber. The spraying is performed in a hot air current. The contact time of the microcapsules in the hot air is very brief and enables avoidance of the coated material from reaching a temperature higher than 40 degrees C. This method by atomization or nebulisation [spray-drying] offers the advantage of a very easy conversion to the industrial scale. The microencapsulation is formed in a single step and can be conducted continuously on large batches. According to the invention, it will be possible advantageously to use as the emulsifier a non-gastro-resistant conventional coating polymer that is to say endowed with filmogenic and emulsifying properties. None of the microcapsules described before the invention posesses an envelope constituted by a polymer with gastro-resistant properties in admixture with other polymers with emulsifying properties. According to the invention, to stablize the emulsion, it will be possible in addition, to use a non-ionic surface active emulsifier such as Tween 80.RTM..
The polymers used in the method according to the invention are in the form of an aqueous solution which enables an emulsion of the oil-in-water type to be produced with the oily liquid. No organic solvent is hence used in the course of the manufacturing method which considerably reduces the risks during handling and also the presence of toxic residues in the finished products.
The appearance of the finished product obtained according to the method of the invention is a powder of which the sizes of the microcapsules constituting it is 25.mu. to 100.mu.. This appearance in the form of powder is particularly advantageous since it can be incorporated either in a formulation in solid form such as tablets, granules, dragees, or in a form to be dispersed in the liquid although the latter may be slightly acid, for example fruit juices, vegetable juices, lemonades.
Other atomization devices useful according to the invention are described, for example, in MARGARET M. L. "Spray drying of food flavors" Perfumer and Flavorist, 8, 49-56; YOUNG R. A. "Reviews the current situation for spray drying encapsulation" J. Foods Londres Janvier (86) p. 31-33, Spray drying encapsulation todays view; REINECCIUS G. A. et al. (1982) "Spray drying of Foods Flavors, J. theory of flavor retention" Perfumer and Flavorist, 7:4, 2-6. Among gastro-resistant polymers useful according to the invention, may be mentioned more particularly cellulose acetyl phthalate [CAP], cellulose acetotrimellitate [CAT], hydroxypropylmethyl cellulose phthalate [HP50 soluble at pH 5, HP55 soluble at pH 5.5] polyvinyl acetyl phthalate, a copolymer of methacrylic acid and acrylic acid such as products of the Eudraget brand, a latex prepared on the base of CAP such as products of the Aquacoat R, Aquateric R brand or again proteins such as giladins. The foregoing list is not exhaustive but illustrates the range of polymers which may be used to produce microcapsules according to the invention. Among useful non-gastro-resistant polymers endowed with emulsifying properties according to the invention, may be mentioned polysaccharide hydrocolloids such as gums, particularly gum arabic, guar gum, Karaya gum, carob gum, maltodextrins or again mixtures of the latter.
Here again, this list is not exhaustive but illustrates simply the range of polymers which may be used in admixture with a gastro-resistant polymer to produce microcapsules according to the invention. More particularly gum arabic, a polysaccharide of high molecular weight, may be mentioned whose principal skeleton is formed of D galactose, highly substituted by rhamnose arabinose groups and salified glucuronic acid groups [calcium, potassium, magnesium]. This hydrocolloid is soluble in water where it develops its properties: texturizing and anticrystallizing, emulsifying, filmogenic and adhesive.
Its usefulness of the same category as that of other gums mentioned above is double according to the present invention:--emulsifying agent for development of an oil/water type emulsion--an encapsulating agent used on oils. In addition there is no limit to the admissable daily doses.
The maltodextrins are obtained by hydrolysis of the starch molecule by a method identical with the preparation of glucose syrups. Starch is a polymer of D-glucose, the linear chains are obtained by 1-4 linkages, the branch chains by linkages of 1-6. The starch molecule degraded by hydrolysis to a more or less advanced stage gives a glucose syrup which will be characterized by the measurement of dextrose equivalent [D.E.].
The maltodextrins DE 20 [glucose syrup] are white powders, soluble in the cold in water, they give solutions of little viscosity. Used in equal proportion with gum arabic for their film forming and encapsulating properties, they enable the viscosity of the polymer solution to be kept at a fairly low level.
In one embodiment, it is possible to use a certain amount of plasticizers in the polymer solution. There may mentioned 1) Triacetin [glycerin triacetate] is a liquid of density of 1.15 and a boiling point of 259 degrees C. It is soluble in 14 parts of water, in alcohol, benzene, chloroform and ether. 2) Propyleneglycol is a clear, colorless, odorless liquid of slightly sweet taste, hygroscopic. It is water miscible. 3) Cetanol
These plasticizers are used at concentrations varying between 10 and 30% of the weight of the coating polymers, they contribute to the flexibility of the film after drying and facilitate the atomization of the emulsion.
In a particular embodiment of the method, the material therefore comprises as a plasticizer triacetin, propyleneglycol or cetanol.
The plasticizer may be used at a concentration varying between 10 and 30% of the weight of the coating material.
Prior to the formation of the emulsion, the solubilisation of the polymers in water is performed if necessary.
By way of gastro-resistant polymer, cellulose acetylphthalate [CAP] is preferably used.
Cellulose acetylphthalate [CAP] is a derivative of cellulose, with acetyl groups and phthalate acid which here are substituted; it is soluble in water, from pH values higher than 5.7. It is insoluble in an acid medium which confers on it its gastro-resistant properties.
According to the invention, it will be advantageously useful in the form of an aqueous solution of 5 to 20%, for example 10% [w/w], into which will be added 3 to 10%, for example 5.6% of ammonia [w/w with the respect to the polymer] to stablize it. Any ammonia is removed by evaporation during the atomization; in the case where residues would be present in the finished product, it is possible to neutralize the latter by washing of the powder with acid.
When the gastro-resistant polymer is cellulose acetylphthalate, the latter is hence solubilized in an aqueous solution at a pH of at least 5.7, for example, from 5.7 to 10.
Generally, the gastro-resistant polymer, particularly cellulose acetylphthalate can be used in the form of a 5 to 20% aqueous solution, in particular 10% [w/w] in a proportion varying between 5 and 15%, preferably between 3 and 8% of dry matter in the emulsion.
The one or more non-gastro-resistant polymers have emulsifying properties, particularly gum arabic and the maltodextrins will advantageously be used so as to reach a final concentration of polymer of 5 to 30%, in particular 15% of dry matter in the emulsion.
The total dry matter in the emulsion corresponds also to the weight of the microcapsule obtained.
According to one embodiment of the method according to the invention, the first mixture of one or more coating polymers a second mixture of the oily liquid to be encapsulated with the non ionic surfaceactive emulsifier as the case may be, is produced and then said first and second mixtures are mixed together and finally plasticizer added as necessary.
The amount of oily liquid engaged in the method would generally represent about 20 to 50%, in particular 30% of the total dry matter in the emulsion.
The non-ionic surface-active emulsifier used in the method will preferably be Tween 80.RTM., for example in a proportion of 0.1 to 1%, in particular 0.5% (weight/weight) of the emulsion.
By way of oily liquid, it is possible, by the method according to the invention, to encapsulate a wide range of oils of various origins saturated or unsaturated, or mixtures of fatty acid or of triglycerides.
In particular, it will be possible to encapsulate food oils recommended by doctors and nutritionists, particularly in order to prevent cardiovascular disorders, such as peanut oil, fish oil rich in unsaturated fatty acids of the (n-3) family (stearidonic eicosapentaenoic and docosahexaenoic acids). There may also be mentioned borage oil rich in gamma-linolenic acid and other unsaturated fatty acids of the family (n-6) which enable the deficiencies of the enzymatic equipment of synthesis of the icosanoids to be offset.
Finally, will be mentioned mixtures of free fatty acids rich in interesting fatty acids, by an enzymatic hydrolysis method which is described in the example of patent FR 89 12980.
In a preferred embodiment in the method according to the invention, the polyunsaturated fatty acids contained in the oily liquid are derived from acids alpha-linolenic and linoleic essential fatty acids. It is preferentially gamma-linolenic acid, arachidonic acid, docesatetraenoic acid, docosapentaenoic acid, stearidonic acid, eicosapentaenioic acid, and docosahexaenoic acid.
All the oils containing naturally one or several essential polyunsaturated fatty acids in free form or in the form of glyceride, are hence particularly suitable. Among the latter, may be mentioned in particular fish oils, such as sardine and cod for the polyunsaturated fatty acids of the family (n-3), and oils from boraga DPO or from blackcurrant seeds, for the essential polyunsaturated fatty acids of the family (n-6).
The encapsulated oily liquid product may contain any active principle that it is desired to introduce into the organism at the level of the intestine, as long as it is liposoluble. There may be mentioned for example vitamins A, D, E and K, coloring agents, antibiotics, but also peptides of interest. There may be mentioned more especially the active principles whose intestinal absorption is facilated by their association with an oil.
It will be noted that, in the case where the oily liquid or the active principle has a disagreable taste or smell, this is the case, for example, with fish oil, the coating masks the latter during administration at the level of the mouth, but also the envelope being gastro-resistant, it prevents its release at the level of the stomach and thereby, disagreable tastes during digestion.
The encapsulation protects the active principle from oxidation, which permits simplified and prolonged storage of the product. To increase this effect, the oily active principle may be mixed with vitamin E (alpha-tocopherol), this is a liposoluble antioxidant. As has been seen, the atomization process used according to the present invention, has the advantage of only exposing the finished product to a high temperature for a very short time (some seconds) which also reduces the risk of oxidation of the active principle.
The microcapsules obtained by the method according to the invention are novel and it is therefore an object of the invention to provide microcapsules by way of novel products, characterized by a solid envelope consisting of a layer of coating material comprising at least one gastro-resistant polymer, said solid envelope containing an oily liquid; and in particular the micro-capsules can be characterized in that they are constituted, in a particular embodiment, by a gastro-resistant polymer in admixture with one or more non- gastro-resistant coating polymers with emulsifying properties.